Genes Linked to SLE, IL-18 Imported From Neanderthals

February 3, 2014

Study of the Neanderthal genome has unearthed some variants associated with rheumatic disease in modern humans. These may trace to early adaptations to a different climate.

Sankararaman S, Mallick S, Dannemann M, et al.The genomic landscape of Neanderthal ancestry in present-day humans. (2014) Nature. Jan 29; doi:10.1038/nature12961

The value of comparative genome studies is that they can look at the human genome through an evolutionary lens, as another way of identifying significant genes. Geneticists have compared the modern human genome to 50,000-year-old Neanderthal DNA, and have found genes that passed from Neanderthals to humans, as the populations migrated from Africa, to East Asia, to Europe.

Most of those Neanderthal genes were purged from the human genome, but several survived because they presumably contributed to fitness. One variant that has remained is associated with systemic lupus erythematosus (SLE). It is among those that affect the function of keratin, which is found in skin, nails and hair, and could have helped the African descendants adapt to a colder climate.

The variation is in the gene for TNPO3, a nuclear import receptor. In previous genome-wide association studies, the substitutions A>C and A>G in this gene were associated with a higher incidence of SLE. The Neanderthal version has an A>G substitution. As with most such single nucleotide polymorphisms (SNPs), the association is small (but statistically significant) and does not prove causation.

Another SNP found in the Neanderthal genome is associated with the proinflammatory cytokine interleukin-18 in Homo sapiens, and two others are associated with Crohn’s disease.

The Neanderthal studies show that the human population split into two subspecies, the Neanderthal and the modern humans. As the modern humans left Africa, they split again into African and European subspecies. In Europe, the Neanderthal and European populations cross-bred, and that’s where the Neanderthal genes entered the modern population.

It is plausible, said Harvard population geneticist Sriam Sankararaman, that some genes in the immune system were better suited to the new environment, but because of presumed tradeoffs, they were more likely to result in autoimmune disease.

It is also plausible, he said, “that alleles that were beneficial became deleterious in a different environment.”